Structural basis of ? chain family receptor sharing at the membrane level

Common ? chain (?c) cytokine receptors, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated upon engagement with a common ?c receptor (CD132) by concomitant binding of their ectodomains to an interleukin. In this work, we find that direct interactions between the transmembrane domains (TMDs) of both the ?c and the interleukin receptors (ILRs) are also required for receptor activation. Moreover, the same ?c TMD can specifically recognize multiple ILR TMDs of diverse sequences within the family. Heterodimer structures of ?c TMD bound to IL-7 and IL-9 receptor TMDs-determined in a lipid bilayer-like environment by nuclear magnetic resonance spectroscopy-reveal a conserved knob-into-hole mechanism of recognition that mediates receptor sharing within the membrane. Thus, signaling in the ?c receptor family requires specific heterotypic interactions of the TMDs.

Automated summary

Common ? chain cytokine receptors, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated by binding to the common ?c receptor (CD132) and also require direct interactions between the transmembrane domains (TMDs) of both the ?c and interleukin receptors (ILRs) for activation. The same ?c TMD can recognize multiple ILR TMDs with diverse sequences, and the heterodimer structures of ?c TMD bound to IL-7 and IL-9 receptor TMDs reveal a conserved recognition mechanism that allows receptor sharing within the membrane.